The conduction system of the human heart is normally automatic, resulting in the contraction of the atria and ventricles by means of electrical impulses that originate in cardiac tissue. The cardiac cycle is separated into the contraction phase (systole) and relaxation phase (diastole). Although the rhythm of the cardiac cycle is intrinsic, the rate of this rhythm is modified by autonomic nerves and hormones such as epinephrine. The autonomic nervous system is comprised of parasympathetic and sympathetic nerves which release neurotransmitters such as acetylcholine and norepinephrine, respectively.
The natural pacemaker of the human heart is located in the posterior wall of the right atrium in a small area, approximately 2 by 5 by 15 mm, referred to as the sinoatrial node (SA node). The SA node initiates the cardiac cycle of systole and diastole phases by generating an electrical impulse that spreads over the right and left atria, causing them to contract almost simultaneously. This electrical impulse, referred to as the pacemaker potential, is created by the depolarization of the myocardial cells of the SA node, which results from changes in membrane permeability to cations. When the cell membrane is depolarized to about −30 mV, an action potential is produced. This impulse then passes to the atrioventricular node (AV node), which is located on the inferior portion of the interatrial septum. The impulse then continues through the atrioventricular bundle, referred to as the bundle of His, which is located at the top of the interventricular septum. The bundle of His divides into right and left branches which lead to the right and left ventricles respectively. Continuous with both branches of the bundle of His are the Purkinje fibers, which terminate within the ventricular walls. Stimulation of these fibers causes the ventricles to contract almost simultaneously and discharge blood into the pulmonary and systemic circulatory systems.
Abnormal patterns of electrical conduction in the heart can produce abnormalities of the cardiac cycle and seriously compromise the function of the heart, sometimes being fatal. For example, patients having such cardiac conduction disturbances may suffer from sick sinus syndrome (SSS), “brady-tachy syndrome,” bradycardia, tachycardia, and heart block. Artificial pacemakers are often used in patients which suffer from these cardiac conduction disturbances.
In SSS, the conduction problem relates to, inter alia, intermittent reentry of the electrical impulse within the nodal tissue, sometimes resulting in rapid heart beats. A dual chamber pacemaker is often used to sense atrial activity and control the ventricle at the appropriate rate.
In some congenital diseases such as “brady-tachy syndrome,” bradycardia, a slow rate of impulse, and tachycardia, a rapid rate of impulse, occur intermittently. The disease can be fatal where long pauses allow premature ventricular contractions (PVCs) to occur in multiples, initiating tachycardia. A pacemaker and/or cardioverter can be used to control episodes of tachycardia, and conventional demand type pacemakers have long been effective in treating bradycardia.
Excessive delay or failure of impulse transmission in abnormally slow impulse conduction is known as heart block. Heart block is often caused by scar tissue disrupting the conduction system. The cardiac impulse is believed to normally spread from the SA node along internodal pathways to the AV node and ventricles within 0.20 seconds. Heart block occurs in three progressively more serious stages. In first-degree heart block, although all impulses are conducted through the AV junction, conduction time to the ventricles is abnormally prolonged. In second-degree heart block, some impulses are conducted to the ventricles, whereas some are not. In third-degree heart block, no impulses from the natural pacemaker are conducted to the ventricles. This results in a slower ventricular contraction rate. The rate of contraction in this case is usually determined by the rate of the fastest depolarizing His-Purkinje cell distal from the block site. Typically, heart rates in third-degree block are in the 20 to 60 bpm range, but can also be as low as zero in some cases.
Arrhythmias resulting from cardiac conduction disturbances can be treated with a variety of drugs that inhibit specific aspects of the cardiac action potentials and inhibit the production or conduction of impulses along abnormal pathways. Drugs used to treat these arrhythmias block the fast Na+ channels (quinidine, procainamide, lidocaine), block the slow Ca++ channel (verapamil), or block β-adrenergic receptors (propranolol).
The cardiac conduction system, or electrical activation of the heart, involves the transfer of current, in the form of chemical ion gradients, from one myocardial cell to another. Conductive proteins in cardiac cells facilitate this transfer of current. Individual cardiac cells express a plurality of gap junction channel proteins, through which ions traverse. The intercellular channels of gap junctions are assembled from individual membrane-spanning connexin proteins, several of which have been cloned and sequenced in mammals. These proteins facilitate the transfer of ions from cell to cell and are responsible for electronic coupling of cells. Saffitz, et al., J. Card. Electrophys., 1995, 6, 498-510.
Connexin proteins comprise a family of related proteins and include, for example, Cx43 (Fishman, et al., J. Cell Biol., 1990, 111, 589-598), and Cx40 and Cx45 (Kanter, et al., J. Mol. Cell Cardiol., 1994, 26, 861-868). Cx43 appears to be the most abundant connexin in the heart, with expression in the ventricle and atrial myocardium, and distal bundle of His and Purkinje fibers, while being absent from the SA node, AV node, and proximal bundle of His. Gourdie, et al., J. Cell Sci., 1993, 105, 985-991, and Davis, et al., J. Am. Coll. Cardiol., 1994, 24, 1124-1132. Cx40 is most abundantly expressed in the atrial myocardium, and in the distal bundle of His and Purkinje fibers, while present at reduced levels in the ventricular myocardium, and the nodes. Gourdie, et al., J. Cell Sci., 1993, 105, 985-991, and Davis, et at, J. Am. Coll. Cardiol., 1994, 24, 1124-1132. Cx45 is moderately expressed in the ventricle and atrial myocardium, and distal bundle of His and Purkinje fibers, while present at lower levels in the SA node, AV node, and proximal bundle of His. Gourdie, et al., J. Cell Sci., 1993, 105, 985-991, and Davis, et al., J. Am. Coll. Cardiol., 1994, 24, 1124-1132. Cx43 and Cx40 connexins are relatively fast conductive proteins, whereas Cx45 is a relatively slow conductive protein.
Gene therapy has recently emerged as a powerful approach to treating a variety of mammalian diseases. Direct transfer of genetic material into myocardial tissue in vivo has recently been demonstrated to be an effective method of expressing a desired protein. For example, direct myocardial transfection of plasmid DNA by direct injection into the heart of rabbits and pigs (Gal, et al., Lab. Invest., 1993, 68, 18-25), as well as of rats (Ascadi, et al., The New Biol., 1991, 3, 71-81), has been shown to result in expression of particular reporter gene products. In addition, direct in vivo gene transfer into myocardial cells has also been accomplished by directly injecting adenoviral vectors into the myocardium. French, et al., Circulation, 1994, 90, 2415-2424, and PCT Publication WO 94/11506.
It has long been desired to effectively treat conduction pathway abnormalities. To this end, conventional procedures including drug therapy, pacemaker technology, or a combination thereof, have been employed. In contrast to these therapeutic procedures, Applicants' invention is directed to treating and/or correcting disturbances in the cardiac conduction pathway by using delivery systems to deliver conduction protein genetic material into myocardial tissue. In patients with cardiac conduction disturbances, it is desirable to locate the problematic area within the heart, and either treat the problematic cells to restore proper cardiac conduction or enhance the cardiac conduction of normal cells surrounding the problematic area. For example, in a patient with heart block, a tract of normal, healthy cells surrounding the scar in the ventricle, which is causing the heart block, is identified and treated by expressing cardiac conduction proteins, such as, for example, gap junction proteins to impart a faster or otherwise enhanced conduction system. In this case, the block can be effectively bridged, or shunted, resulting in a QRS of a width intermediate between a normally conducted beat and a PVC.